Insulin is a hypoglycemic hormone. Insulin dependent diabetes is caused by selective destruction of insulin-producing cells (islet β-cells) through immunological mechanisms, and its onset is known to result in hyperglycemia, which causes various disorders. In conventional therapy, preparations of the undersupplied insulin are administered (injected) to compensate for the shortage of insulin to redress hyperglycemia. However, strict blood sugar control is difficult in insulin-based therapies, which can lead to over-administration that can cause fatal hypoglycemia. After the onset of diabetes, diabetic vascular complications progress (such as retinopathy, nephropathy, and neuropathy). Conventional therapeutic methods such as insulin injections cannot halt this progress, leading to therapeutically serious problems. Blood sugar is physiologically controlled chiefly by the regulatory mechanism of islet β-cells; however, in insulin dependent diabetes, the deletion of these islets results in violent ups and downs in blood sugar level, causing the above-described clinical symptoms.
In recent years, Europe and the United States have started clinical application of islet transplantation, where pancreatic islets of Langerhans (islets) are transplanted as a means for treating diabetes. This attempts treatment not by administering insulin, but by transplanting insulin-producing cells. The practical procedure of clinical islet transplantation is as follows: ultrasound-guided percutaneous, transpulmonary portal vein catheterization is carried out under local anesthesia; and then donor islets are transplanted to the liver via the catheter. The islet grafts survive at the end of the portal vein, and control blood sugar level by secreting insulin. When successful, islet transplantation restores normal blood sugar to diabetic recipients, such that insulin treatment becomes unnecessary. To date, however, successful cases of clinical islet transplantation are limited. Further, transplantation to a single recipient requires islets isolated from the pancreas of two or three donors. Specifically, since islet function disorders that appear immediately after transplantation reduce graft viability, islet transplantation from a single donor to a single recipient is insufficient, and thus, transplantation from two to three donors to a single recipient is carried out. Some reports suggest only 20% to 30% of transplanted grafts survive. Details of these functional disorders remain unclear, but they pose an extremely serious problem in terms of improving the results of clinical islet transplantation.
Conventionally, islet transplantation has been performed using islets isolated from the pancreases of brain-dead donors or donors under cardiac arrest. Recent reports also describe successful cases of living donor islet transplantation, in which islets are isolated and purified from a portion of pancreas excised from healthy donors and transplanted to diabetic patients. Such living donor islet transplantation is invasive and a burden for donors. Thus, it is preferable to enable treatments that suppress damage to transplanted islets just after transplantation and that use fewer donor islets.
IL-6 is a cytokine called B-cell stimulating factor 2 (BSF2) or interferon β2. IL-6 was discovered as a differentiation factor involved in the activation of B-cell lymphocytes (Non-patent Document 1), and was later revealed to be a multifunctional cytokine that influences the function of various cells (Non-patent Document 2). IL-6 has been reported to induce maturation of T lymphocyte cells (Non-patent Document 3).
IL-6 transmits its biological activity via two kinds of proteins on the cell. One of the proteins is the IL-6 receptor which is a ligand binding protein to which IL-6 binds and has a molecular weight of about 80 kDa (Non-patent Documents 4 and 5). In addition to a membrane-bound form that penetrates and is expressed on the cell membrane, the IL-6 receptor is present as a soluble IL-6 receptor which mainly consists of the extracellular region of the membrane-bound form.
The other is the membrane protein gp130 which has a molecular weight of about 130 kDa and is involved in non-ligand binding signal transduction. The biological activity of IL-6 is transmitted into the cell through formation of the IL-6/IL-6 receptor complex by IL-6 and IL-6 receptor and binding of the complex with gp130 thereafter (Non-patent Document 6).
IL-6 inhibitors are substances that inhibit the transmission of IL-6 biological activity. Until now, antibodies against IL-6 (anti-IL-6 antibodies), antibodies against IL-6 receptors (anti-IL-6 receptor antibodies), antibodies against gp130 (anti-gp130 antibodies), IL-6 variants, partial peptides of IL-6 or IL-6 receptors, and such are known.
There are several reports regarding the anti-IL-6 receptor antibodies (Non-patent Documents 7 and 8, Patent Documents 1-3). A humanized PM-1 antibody, which had been obtained by transplanting into a human antibody, the complementarity determining region (CDR) of mouse antibody PM-1 (Non-patent Document 9), which is one of anti-IL-6 receptor antibodies, is known (Patent Document 4).
Information on prior-art documents related to the present invention is described below:    [Non-patent Document 1] Hirano, T. et al., Nature (1986) 324, 73-76    [Non-patent Document 2] Akira, S. et al., Adv. in Immunology (1993) 54, 1-78    [Non-patent Document 3] Lotz, M. et al., J. Exp. Med. (1988) 167, 1253-1258    [Non-patent Document 4] Taga, T. et al., J. Exp. Med. (1987) 166, 967-981    [Non-patent Document 5] Yamasaki, K. et al., Science (1988) 241, 825-828    [Non-patent Document 6] Taga, T. et al., Cell (1989) 58, 573-581    [Non-patent Document 7] Novick, D. et al., Hybridoma (1991) 10, 137-146    [Non-patent Document 8] Huang, Y W. et al., Hybridoma (1993) 12, 621-630    [Non-patent Document 9] Hirata, Y et al., J. Immunol. (1989) 143, 2900-2906    [Patent Document 1] International Patent Application Publication No. WO 95/09873    [Patent Document 2] French Patent Application No. FR 2694767    [Patent Document 3] U.S. Pat. No. 5,216,128    [Patent Document 4] WO 92/19759